Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope

Alexander Rouvinski (1) , Wanwisa Dejnirattisai (2) , Pablo Guardado-Calvo (1) , Marie-Christine Vaney (1) , Arvind Sharma (1) , Stéphane Duquerroy (1) , Piyada Supasa (2) , Wiyada Wongwiwat (2) , Ahmed Haouz (3) , Giovanna Barba-Spaeth (1) , Juthathip Mongkolsapaya (2, 4) , Félix A. Rey (1) , Gavin R. Screaton (2)

1 Virologie Structurale - Structural Virology
2 Division of Immunology and Inflammation, Department of Medicine
3 Protéopole
4 Siriraj Hospital, Mahidol University

A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.

Keywords: Dengue virus; X-ray crystallography; Vaccines; Viral infection

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Immunology; Vaccinology; Life Sciences [q-bio]; Microbiology and Parasitology; Virology

Alexander Rouvinski, Wanwisa Dejnirattisai, Pablo Guardado-Calvo, Marie-Christine Vaney, Arvind Sharma, et al.. Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope. Nature Communications, 2017, 8, pp.15411. ⟨10.1038/ncomms15411⟩. ⟨pasteur-01540166⟩